1. Field of the Invention
This invention relates to the controlled release of macromolecules, particularly hydrophilic macromolecules. More specifically, it relates to the delayed/sustained release of pharmaceutical compositions, particularly polypeptides such as luteinizing hormone-releasing hormones ("LH-RH"), mammalian growth hormones, mammalian growth hormone-releasing hormones, polypeptides having thymosin-like activity, and the analogs thereof. Specifically, the invention relates to drug delivery devices having an initially partially-hydrated, non-biodegradable hydrogel rate-limiting membrane. These delivery systems, which may include ocular inserts and implantable devices, delay the release of macromolecules until after placement in a delivery environment, and then facilitate a sustained, preferably zero-order release thereof.
2. Background Information
The sustained release of active agents is known to be of value. Particularly in the administration of certain pharmaceuticals, long-term drug delivery has been shown to be most effective in that constant serum levels are obtained and patient compliance is improved. Delaying the release of such agents is also desirable in that an immediate release upon placement in the delivery environment can result in unacceptably high initial concentrations of a drug at the situs of implantation or use.
The examination of synthetic hydrogels for potential biomedical applications (including potential use in certain drug delivery devices) has given rise to various theories regarding mechanisms of diffusion. Lee, Jhon and Andrade have proposed that there are three classes of water in hydrogels, using polyHEMA (hydroxyethyl methacrylate) as their model [Nature of Water in Synthetic Hydrogels, J. Colloid & Interface Sci., 51 (2): 225-231 (1975)]. The first 20% of hydrogel water content, called "Z water", was said to be bound to the polymer matrix. The next 10-12% of water content, called interfacial or "Y water", is partially affected by the polymer matrix. Any additional water imbibed by the gel is relatively unaffected by the polymer matrix; it is called bulk or "X water".
The Lee, et al. model was expanded upon by Kim, Cardinal, Wisniewski and Zentner [Solute Permeation Through Hydrogel Membranes: Hydrophilic vs. Hydrophobic Solutes, ACS Symposium Series (Water in Polymers), 127 (20): 347-359 (1980)]. They concluded that the diffusion coefficients for hydrophilic solutes through hydrogel membranes depends on molecular size and water content; permeation in pure polyHEMA and in polyHEMA crosslinked with a low mole percent of ethyleneglycoldimethacrylate ("EGDMA") was via the pore mechanism, i.e., through the bulk-type water. Hydrophobic solutes were said to diffuse via both pore and partition mechanisms, i.e., respectively through the bulk-type water, and through the interfacial-type and bound-type water. Neither article, however, included any suggestion as to how such diffusion characteristics might be applied to the design of a delayed/sustained delivery device.
Wood, Attwood and Collett have described a model for diffusion of the small hydrophobic molecule salicylic acid (the solute) in hydrogels [The influence of gel formulation on the diffusion of salicylic acid in polyHEMA hydrogels, J. Pharm. Pharmacol., 34: 1-4 (1982)]. Radioactively labelled salicylic acid was added to a HEMA monomer solution and polymerized in situ. The water contents of the resulting gels were measured. Diffusion was measured by quantifying migration of the solute to a gel placed in contact with the sample gels. It was concluded that diffusion occurred primarily through the polymer's pores via the hydrating liquid at higher levels of hydration (more than 31%). At hydration levels below 31%, diffusion was said to occur by dissolution of the solute within the polymer segments; crosslinker concentration did not have any significant effect on diffusion. This was correlated to a change in pore size proportional with percent hydration. Wood, et al. did not, however, offer any teaching as to the effects of percent hydration on delayed/sustained release of hydrophilic macromolecular compositions. For another treatment of the interaction of pore size and diffusion, see Wisniewski and Kim [J. Membrane Sci., 6: 299-308 (1980)].
Controlled and sustained release compositions are known in the art for progesterone. [See Mack, et al., Topics in Pharm. Sci., pp. 265-275 (1983). ] A variety of devices have been described, for example, in the article by Cardinal, Kim, Song, Lee and Kim [Controlled Release Drug Delivery Systems from Hydrogels: Progesterone Release from Monolithic, Reservoir, Combined Reservoir-Monolithic and Monolithic Devices with Rate Controlling Barriers, AIChE Symposium Series, 77: 52-61 (1981)].
Microporous membranes (some including hydrogels) have been used as rate-limiting barriers for such devices, including implants, ocular inserts, coated intrauterine devices and the like, e.g., as described in U.S. Pat. Nos. 3,416,530 (to Ness--entitled "Eyeball Medication Dispensing Tablet"); 3,551,556 (to Kliment, et al.--entitled "Carriers for Biologically Active Substances"); 3,618,604 (to Ness--entitled "Ocular Insert"); 3,828,777 (to Ness--entitled "Microporous Ocular Device"); and 4,548,990 (to Mueller, et al.--entitled "Crosslinked, Porous Polymers for Controlled Drug Delivery").
In U.S. Pat. No. 3,993,072 (to Zaffaroni--entitled "Microporous Drug Delivery Device") and in its parent patents 3,948,254 (entitled "Novel Drug Delivery Device") and 3,854,380 (entitled "Drug-Delivery System"), drug delivery systems are disclosed including a solid inner matrix containing a drug and surrounded by a wall formed of a polymeric membrane (the '072 and '254 patents call for a microporous membrane, the pores of which contain a drug-release-rate-controlling medium).
Some sustained release devices have been described for the delivery of hydrophilic macromolecules, such as polypeptides. For example, European Patent Application Publication No. 0,092,918 (to Churchill, et al.--entitled "Continuous Release Formulations") describes the continuous release of, e.g., luteinizing hormone-releasing hormone, growth hormones and growth hormone releasing factor, from a hydrophobic/hydrophilic non-crosslinked copolymer in which the hydrophobic component is biodegradable and the hydrophilic component may or may not be biodegradable. The composition is described as being capable of absorbing water to form a hydrogel when placed in an aqueous, physiological-type environment.
These prior devices depend on the relationship between the drug's diffusivity in the reservoir, its diffusivity in the delivery environment, and its diffusivity through the membrane. In other words, the diffusivity through the membrane has to be the least of the three, in order for the membrane to serve as a rate-limiting barrier. They all generally rely on Fick's First Law of Diffusion, in which the flux of a solute through a membrane is related to the area and thickness of the membrane, the permeability coefficient of the solute for that membrane material, and the concentration of the solute.
In attempts to apply the prior art relating to hydrogel-based delivery devices to macromolecules, it was discovered that none of the prior devices solve the following problems:
(i) Such devices release macromolecules as soon as the device is in place.
(ii) Such devices cause an initial spike of drug release in the delivery environment.
(iii) Such devices are difficult to handle during implantation, due to their flexibility.
(iv) Non-hydrated (or xerogel) devices are relatively fragile as compared to hydrated hydrogel devices, in that their rate controlling membranes are quite brittle and tend to chip or crack when handled (e.g., during implantation), potentially destroying the sealed reservoir environment required for zero-order release.
The present invention solves all of the foregoing problems through the use of an initially partially-hydrated, non-biodegradable, hydrogel rate-limiting membrane surrounding a suitable carrier and a macromolecular composition.